Influence of prenatal undernutrition on the effects of clozapine and aripiprazole in the adult male rats: Relevance to a neurodevelopmental origin of schizophrenia?

• Published in: European journal of pharmacology Vol. 667; no. 1; pp. 402 - 409
• Main Authors: Guillemot, Johann, Lukaszewski, Marie-Amélie, Montel, Valérie, Delahaye, Fabien, Mayeur, Sylvain, Laborie, Christine, Dickes-Coopman, Anne, Dutriez-Casteloot, Isabelle, Lesage, Jean, Breton, Christophe, Vieau, Didier
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 30.09.2011; Elsevier
• Subjects: Adult and adolescent clinical studies; adults; Animals; Antipsychotic Agents - pharmacology; Aripiprazole; Atypical neuroleptics; Biological and medical sciences; blood glucose; Body Weight - drug effects; Body weight gain; chronic diseases; Clozapine; Clozapine - pharmacology; Corticosterone; Data processing; Disease Susceptibility - chemically induced; Eating - drug effects; Energy metabolism; Female; Food; food intake; Gene Expression Regulation - drug effects; genes; Glucose; Hormones - blood; Hypothalamus; Hypothalamus - drug effects; Hypothalamus - metabolism; Insulin; insulin secretion; leptin; Life Sciences; Male; males; Malnutrition; Maternal undernutrition; Medical sciences; Mental disorders; Metabolic diseases; Metabolic disorders; Metabolic syndrome; Miscellaneous; mothers; Nervous System - drug effects; Nervous System - growth & development; Neuroleptics; Obesity - genetics; Other metabolic disorders; Other nutritional diseases (malnutrition, nutritional and vitamin deficiencies...); patients; pharmacology; Pharmacology. Drug treatments; Piperazines - pharmacology; Plasma levels; Polymerase chain reaction; Pregnancy; Prenatal Nutritional Physiological Phenomena; Progeny; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychoses; Quinolones - pharmacology; Rats; Rats, Wistar; reverse transcriptase polymerase chain reaction; Schizophrenia; Schizophrenia - metabolism; Schizophrenia - pathology; Schizophrenia - physiopathology; Secretion; Undernutrition; weight gain; Schizophrenia; Hypothalamus; Metabolic syndrome; Atypical neuroleptics; Maternal undernutrition; Endocrinopathy; Partial agonist; Dibenzodiazepine derivatives; Atypical antipsychotic; Rat; Neuroleptic; Psychotropic; Central nervous system; Quinolinone derivatives; Cardiovascular disease; Male; Aripiprazole; Encephalon; Psychosis; Prenatal; 5-HT1A Serotonine receptor; Antagonist; Malnutrition; 5-HT2A serotonin receptor; Rodentia; Nutrition disorder; Metabolic diseases; Clozapine; Vertebrata; Mammalia; D2 Dopamine receptor; Adult animal
• ISSN: 0014-2999; 1879-0712; 1879-0712; 0014-2999
• DOI: 10.1016/j.ejphar.2011.04.011

Epidemiological and experimental data indicate that maternal undernutrition may sensitize the offspring to the apparition of chronic diseases such as metabolic syndrome and schizophrenia, suggesting that these pathologies may have a developmental origin. To test this hypothesis, we have compared the effects of a 4 weeks treatment of clozapine (30 mg/kg once daily, p.o.) or aripiprazole (10 mg/kg once daily, p.o.) on metabolic and hormonal parameters in 4-month-old male animals from control or 70% prenatally food-restricted mothers (FR30 model). Both neuroleptics did not markedly modify body weight gain and food intake in both controls and FR30 rats. Clozapine decreased insulin secretion in both groups but significantly diminished leptin, corticosterone and glucose plasma levels only in FR30 animals. Aripiprazole decreased corticosterone plasma levels only in FR30 animals. Using quantitative RT-PCR array containing 84 obesity-related genes, we identified several genes involved in energy metabolism regulation whose expression was modified by clozapine or aripiprazole in adult male rat hypothalami. In addition, we demonstrated that expression of some of these genes was differentially affected by each neuroleptic in the hypothalamus of both FR30 and control animals. Although no marked metabolic alterations were observed in both control and FR30 animals after clozapine or aripiprazole treatment, our data indicate that offspring from undernourished mothers exhibit a modified sensitivity to atypical neuroleptics. Our results do not rule out a putative developmental origin of schizophrenia and may help to understand the way by which atypical neuroleptics, such as clozapine, sensitize schizophrenic patients to the development of metabolic disorders.